Project Summary This grant seeks to evaluate striatal dopaminergic functioning during reward processing in autism spectrum disorder (ASD) through the use of simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Preclinical research strongly implicates impaired mesolimbic dopamine functioning in the etiology of ASD. Additionally, fMRI evidence suggests that ASD is characterized by striatal hypoactivation during reward processing. However, since fMRI is sensitive only to blood oxygen level dependent signals, it is not known whether striatal hypoactivation during reward processing in ASD observed with fMRI is associated with impaired striatal dopamine functioning. Additionally, it is not known whether striatal hypoactivation during reward processing in ASD is linked to reduced phasic dopamine release or to reduced background dopamine tone that inhibits phasic dopamine release. Finally, whether impaired dopamine functioning in ASD is related to ASD symptom severity is poorly understood. These are critical gaps in our understanding of ASD pathophysiology given that studies of ASD model organisms are starting to pinpoint the specific molecular mechanisms that are implicated in ASD, whereas not a single molecular imaging study to date has targeted the mesolimbic dopamine system in ASD. PET imaging is ideally suited to bridge this gap between preclinical ASD research and clinical neuroimaging studies of reward processing in ASD. We propose to collect simultaneous PET and fMRI from a cohort of young adults with ASD and matched typically developing young adults during a reward processing task using the D2/D3 dopamine receptor antagonist [11C]raclopride. The use of a bolus+infusion radiotracer administration protocol will provide increased sensitivity towards measuring dopamine release, a critical feature of this project. We will evaluate background dopaminergic tone and phasic dopaminergic release in response to incentives in ASD (Aim 1), correlations between PET-derived measures of D2/D3 striatal receptor occupancy and fMRI-derived measures of striatal activation (Aim 2), and relationships between PET-derived measures of D2/D3 striatal receptor occupancy and symptom severity in the ASD group (Aim 3). This project represents the first step of our long- term goal to establish a program of PET ASD research that is positioned to translate findings of novel compounds that rescue receptor binding potentials in preclinical ASD models to clinical ASD studies of target engagament by these same compounds. This pipeline of preclinical drug discovery to clinical drug evaluation is ideally suited to PET neuroimaging because of its capacity to measure classes of receptors targeted by specific ligands.